The continuing goal of this project is to define the oncogenic effects of radiation on the mammary glands at the cellular and sub-cellular levels. Mammary cancer is a major malignant disease among American women and a major cause of morbidity and mortality among those exposed to ionizing radiation. We hypothesized that the mammary cells from which malignant tumors arise are the same clonogenic cell sub-population necessary to tissue repair and repopulation following radiation injury. We have developed quantitative rat mammary cell transplantation and endocrine manipulation procedures and short- term culture techniques to measure the concentration of mammary clonogens, i.e. the cells which when transplanted to hormonally modified recipients give rise to multi-cellular clonal glandular units. With these techniques we have defined the radiation dose-survival response of mammary clonogens after exposure to radiation, and have demonstrated that radiogenic initiation of cancer is a common cellular event and is dependent on the number of clonogenic cells present at the time of radiation exposure. During this grant period, we will: 1) determine whether the radiation-induced initiating lesion is repairable; 2) quantitate the relationship between initiated cell number, radiation dose and carcinoma incidence; 3) determine the effect of donor age on the susceptibility of the mammary clonogens to radiogenic initiation; 4) further purify the clonogenic cells and their properties; and 5) investigate karyotypic changes in the clonogens and their progeny during promotion/progression to overt cancer.